The human gut is a complex environment that contains a multitude of microorganisms that are collectively termed the microbiome. Multiple factors have a role to play in driving the composition of human gut bacterial communities either toward homeostasis or the instability that is associated with many disease states. One of the most important forces are likely to be bacteriophages, bacteria-infecting viruses that constitute by far the largest portion of the human gut virome. Despite this, bacteriophages (phages) are the one of the least studied residents of the gut. This is largely due to the challenges associated with studying these difficult to culture entities. Modern high throughput sequencing technologies have played an important role in improving our understanding of the human gut phageome but much of the generated sequencing data remains uncharacterised. Overcoming this requires database-independent bioinformatic pipelines and even those phages that are successfully characterized only provide limited insight into their associated biological properties, and thus most viral sequences have been characterized as “viral dark matter.” Fundamental to understanding the role of phages in shaping the human gut microbiome, and in turn perhaps influencing human health, is how they interact with their bacterial hosts. An essential aspect is the isolation of novel phage-bacteria host pairs by direct isolation through various screening methods, which can transform in silico phages into a biological reality. However, this is also beset with multiple challenges including culturing difficulties and the use of traditional methods, such as plaquing, which may bias which phage-host pairs that can be successfully isolated. Phage-bacteria interactions may be influenced by many aspects of complex human gut biology which can be difficult to reproduce under laboratory conditions. Here we discuss some of the main findings associated with the human gut phageome to date including composition, our understanding of phage-host interactions, particularly the observed persistence of virulent phages and their hosts, as well as factors that may influence these highly intricate relationships. We also discuss current methodologies and bottlenecks hindering progression in this field and identify potential steps that may be useful in overcoming these hurdles.
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